Despite progress in planning and delivery of radiation therapy, treatment of abdominal tumors is often dose-limited by the risk of intestinal toxicity (radiation enteropathy). Radiation enteropathy is characterized by epithelial barrier breakdown, mucosal inflammation, and progressive fibrosis. The previous notion that radiation enteropathy develops exclusively as a result of crypt cell death has been supplanted. Instead, it is now widely recognized that many functional and secondary changes contribute to the pathophysiological manifestations of radiation enteropathy. These changes are promising targets for interventions aimed at preventing and/or reducing radiation-induced bowel toxicity. In the intestine, there are important connections between the nervous system and cells of the immune system. Notably, sensory nerves and resident mast cells in the bowel mucosa constitute a functional unit that regulates many physiological and pathological processes through bidirectional interactions. We recently demonstrated that crosstalk between intestinal sensory nerves and mast cells substantially regulate the development of radiation enteropathy. The proposed research will use validated genetic and pharmacologic approaches, coupled with quantitative structural endpoints and molecular methods, to systematically dissect the mechanisms by which these neuroimmune interactions modulate the intestinal radiation response. The project will 1) examine the role of calcitonin gene-related peptide (CGRP) in the crosstalk between sensory nerves and mast cells; 2) determine to what extent thrombin regulates the protective properties of enteric sensory nerves; 3) assess the role of the endothelin (ET) system in the mechanisms by which mast cells regulate radiation enteropathy development; and finally 4) investigate the role of proteinase activated receptor 2 (PAR2), a receptor that is activated by mast cell proteinases, in radiation-induced intestinal inflammation and/or fibrosis. These experiments are based on data generated during the previous funding period and will provide substantial new insight into the basic pathogenesis of the intestinal radiation response. Advancing the understanding of the basic mechanisms underlying radiation enteropathy is critical for identifying targets for intervention. This research will thus facilitate development of specific strategies to minimize intestinal radiation toxicity in the clinic and thereby make radiation therapy safer and more effective. This research program is focused on issues that are important to cancer survivors, specifically on how to make radiation therapy safer and more effective. PUBLIC HEALTH RELEVANCE: The overall goal of this specific project is to investigate how interactions between the immune system and nervous system in the intestine affect the development of radiation injury. These studies will generate new insight into the mechanisms by which intestinal radiation injury occurs and help develop strategies to minimize such injury.